A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of a Novel CCR5 Antagonist, UK-427,857, in Combination With Optimized Background Therapy Versus Optimized Background Therapy Alone for the Treatment of Antiretroviral-Experienced HIV-1 Infected Subjects.

Maraviroc (UK-427,857), a selective and reversible CCR5 coreceptor antagonist, has been shown
to be active in vitro against a wide range of clinical isolates (including those resistant to
existing classes). In HIV-1 infected patients, maraviroc (UK-427,857) given as monotherapy
for 10 days reduced HIV-1 viral load by up to 1.6 log, consistent with currently available
agents. Safety and toleration have been studied in over 400 subjects for up to 28 days at 300
mg twice daily. No significant effects were seen on the QTc interval. The purpose of this
study is to evaluate the antiretroviral activity of maraviroc (UK-427,857) in HIV infected,
treatment experienced patients who are failing their current antiretroviral regimen and are
infected with R5-tropic virus exclusively. This study will involve more than 100 centers from
the US and Canada to achieve a total randomized subject population of 500 subjects. Patients
will be randomly (2:2:1) assigned to one of three groups: Optimized Background Therapy [OBT
(3-6 drugs based on treatment history and resistance testing)] + maraviroc (UK-427,857) 150
mg taken once daily, OBT + maraviroc (UK-427,857) 150 mg taken twice daily, or OBT alone. The
study will enroll over approximately a 9 month period with 48 weeks of treatment. This may be
extended for an additional year depending on the results at 48 weeks. Physical examinations
will be performed at study entry, weeks 4, 8, 12, 16, 20, 24, 32, 40, and 48. Blood samples
will also be taken at study entry, weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, and 48.
Additionally, blood samples will be drawn twice, at least 30 minutes apart, at weeks 2 and 24
for maraviroc (UK-427,857) pharmacokinetic analysis. As part of this clinical study a blood
sample will also be taken for non-anonymized pharmacogenetic analysis. Patients will undergo
a 12-lead electrocardiogram at study entry, weeks 24 and 48.